Orexin, also known as hypocretin, orexin peptide, comprises orexin A and orexin B (or hypocretin-1 and hypocretin-2), which is a neuropeptide secreted by the hypothalamus, its main physiological functions are: 1. regulation of feeding, orexin can significantly promote eating, which shows a dose-dependent response with the food intake, and activates neurons regulating feeding; 2. regulation of energy metabolism, orexin can significantly increase the metabolic rate; 3. regulation of sleep-wake, orexin can inhibit rapid eye movement sleep and extend wake time, and it can promote sleep that the effect of orexin are blocked; 4. regulation of endocrine, orexin have a very significant effect on the endocrine of pituitary hormones; 5. relationship with a sense of reward, learning and memory; 6. promotion of gastric acid secretion 7. promotion of an increase in drinking water 8. elevation of blood pressure; 9. playing an important role in reward system and drug addiction mechanism, and the like. (Piper, et al., The novel brain neuropeptide, orexin-A, modulates the sleep-wake cycle of rats. Eur. J. Neuroscience, 2000, 12(2), 726-730; and Sakurai, T., et al., The neural circuit of orexin (hypocretin): Maintaining sleep and wakefulness. Nature Review Neuroscience, 2007, 8: 171181).
Orexin produces physiological effects by acting on orexin receptor (OXR). Orexin receptor is a G-protein coupled receptor, which has two types, called OX1 receptor and OX2 receptor respectively, wherein, OX1 receptor is selective for orexin A, and OX2 is non-selective for orexin A and orexin B (Sakurai T. et al., Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell, 1998, 92(4): 573-585). OX1 receptors and OX2 receptors almost only exist in brain tissue, and are selectively expressed in the brain, wherein OX1 receptor is expressed at high density in locus coeruleus, which is a nuclei originis of noradrenergic neurons, and OX2 receptor is expressed at high density in tuberomammillary nucleus, which is a nuclei originis of histaminergic neurons. Expression of both OX1 receptor and OX2 receptor can be found in raphe nuclei, which are nuclei originis of serotonergic neurons, and found in ventral tegmental area, which are nuclei originis of dopaminergic neurons. Moreover, OX2 receptor also can be found in brain stem cholinergic neurons, which are responsible for regulating rapid eye movement sleep, and have an impact on their nuclear activities. (Marcus, J. N. et al., Differential expression of orexin receptors 1 and 2 in the rat brain. J. Comp. Neurol., 2001, 43 5(1): 6-25; and Trivedi, P. et al., Distribution of orexin receptor mRNA in the rat brain. FEBS Lett., 1998, 438(1-2): 71-75).
Thus, orexin receptors have an important significance in pathology, and associated with a variety of diseases, such as a sleep disorder, depression, anxiety, a panic disorder, an obsessive-compulsive disorder, an affective disorder, depressive neurosis, anxiety neurosis, a mood disorder, a panic attack disorder, a behavior disorder, emotional disturbance, a post-traumatic stress disorder, sexual dysfunction, psychosis, schizophrenia, manic depression, a mental disorder, dementia, drug dependence, addiction, a cognitive disorder, Alzheimer's disease, Parkinson's disease, a movement disorder, an eating disorder, headache, migraine, pain, a digestive system disease, epilepsy, inflammation, a cardiovascular disease, diabetes, a metabolic disease, an immunity-related disease, an endocrine-related disease and high blood pressure, and so on.